JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-19
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IF 10.6
Tang Bo,Wang Qiuxiang,Zhang Guowei,Zhang Aiwen,Zhu Lu,Zhao Rongrong,Gu Hongwei,Meng Jie,Zhang Junfang,Fang Guihua
Traditional eye drops are administered via topical instillation. However, frequent dosing is needed due to their relatively rapid precorneal removal and low ocular bioavailability. To address these issues, stearoyl L- carnitine-modified nanoemulsions (SC-NEs) were fabricated. The physicochemical properties of SC-NEs in terms of size, morphology, zeta potential, encapsulation efficiency, and in vitro drug release behavior were characterized. The cellular uptake and mechanisms of SC-NEs were comprehensively studied in human corneal epithelial cells and the stearoyl L- carnitine ratio in SC-NEs was optimized. The optimized SC-NEs could target the novel organic cation/carnitine transporter 2 (OCTN2) and amino acid transporter B (0 +) (ATB 0,+ ) on the corneal epithelium, which led to superior corneal permeation, ocular surface retention ability, ocular bioavailability. Furthermore, SC-NEs showed excellent in vivo anti-inflammatory efficacy in a rabbit model of endotoxin-induced uveitis. The ocular safety test indicated that the SC-NEs were biocompatible. In general, the current study demonstrated that OCTN2 and ATB 0,+ -targeted nanoemulsions were promising ophthalmologic drug delivery systems that can improve ocular drug bioavailability and boost the therapeutic effects of drugs for eye diseases. Graphical Abstract
研究领域:
药剂学
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眼科学
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药物递送系统
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纳米技术
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高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2025
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IF 5.6
Hailun Zheng,Xiaoyan Mao,Zhiwei Chen,Linying Wang,Fuxiang Shangguan,Zihao Tao,Jinyao Ye,Weilan Cao,Qing Yao,Lili Yan,Ruijie Chen,Shihui Bao,Longfa Kou
Chemotherapy remains one of the main treatments for gastric cancer, but the efficacy of 5-fluorouracil (5-FU) is limited by drug resistance. Ferroptosis is a unique mode of regulated cell death characterized by iron accumulation and lipid peroxidation, and its induction by aberrant STAT3 signaling may contribute to chemotherapy resistance. Cryptotanshinone (Cpt) is a bioactive compound extracted from Salvia miltiorrhiza that acts as a STAT3 inhibitor and has shown efficacy against several malignancies, endowing its potential as an agent to overcome the chemotherapy of gastric cancer. Importantly, cancer cells—especially drug-resistant cells—often upregulate amino acid transporters to import indispensable nutrients that support rapid proliferation, and therefore these transporters could guide the target delivery of chemotherapeutics for enhanced delivery efficiency. Here, we developed an amino acid transporter-targeted nanoplatform (F/C@Trp-NPs) co-loaded with 5-FU and Cpt to target the SLC6A14 (ATB 0,+ ) transporter, which is abnormally upregulated in gastric cancer cells, and evaluated its anticancer effects. The F/C@Trp-NPs significantly inhibited gastric cancer cell proliferation in vitro, consistent with the in vivo results. This study provides a promising new therapeutic strategy for gastric cancer.
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Bioactive Materials
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2021
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IF 14.593
Longfa Kou,Xinyu Jiang,Yingying Tang,Xing Xia,Yingtao Li,Aimin Cai,Hailun Zheng,Hailin Zhang,Vadivel Ganapathy,Qing Yao,Ruijie Chen
Reprogramed cellular metabolism is one of the most significant hallmarks of cancer. All cancer cells exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis. The resultant enhanced availability of amino acids supports the reprogramed metabolic pathways and fuels the malignant growth and metastasis of cancers by providing energy and critical metabolic intermediates, facilitating anabolism, and activating signaling networks related to cell proliferation and growth. Therefore, pharmacologic blockade of amino acid entry into cancer cells is likely to have a detrimental effect on cancer cell growth. Here we developed a nanoplatform ( [email protected] ) to therapeutically target two transporters, SLC6A14 (ATB 0,+ ) and SLC7A5 (LAT1), that are known to be essential for the sustenance of amino acid metabolism in most cancers. The [email protected] uses tryptophan to guide SLC6A14-targeted delivery of JPH203, a high-affinity inhibitor of SLC7A5. In the process, SLC6A14 is also down-regulated. We tested the ability of this strategy to synergize with the anticancer efficacy of lapatinib, an inhibitor of EGFR/HER1/HER2-assocated kinase. These studies show that blockade of amino acid entry amplifies the anticancer effect of lapatinib via interference with mTOR signaling, promotion of apoptosis, and suppression of cell proliferation and metastasis. This represents the first study to evaluate the impact of amino acid starvation on the anticancer efficacy of widely used kinase inhibitor.
研究领域:
肿瘤学
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药理学
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纳米技术
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细胞生物学
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分子生物学
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JOURNAL OF CONTROLLED RELEASE
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2019
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IF 7.901
Zhenjie Wang,Dongxu Chi,Xingchen Wu,Yingli Wang,Xinxin Lin,Zhaochu Xu,Hongzhuo Liu,Jin Sun,Zhonggui He,Yongjun Wang
As the demand for nutrients in malignant proliferation of tumors increases, the L-type amino acid transporter 1(LAT1) and amino acid transporter B 0,+ (ATB 0,+ ) of tumor cells are more highly expressed than normal cells which can be used as new targets for active targeting of cancer. However, drug delivery systems often require multi-target design to achieve simultaneous targeting of different receptors or transporters due to the heterogeneity of the tumor. Here we utilized triethylamine-sucrose octasulfate gradient to actively encapsulate irinotecan into the introliposomal aqueous phase. Targeted ability was achieved through inserting different amino acids modified polyethylene glycol monostearate into the liposomes , and found that glutamate-liposomes can be targeted to LAT1, lysine-liposomes can be targeted to ATB 0,+ , and inspiringly, tyrosine-liposomes can be simultaneously targeted to LAT1 and ATB 0,+ . The tyrosine-modified liposomes showed the highest cellular uptake in BxPC-3 and MCF-7 cells which were highly expressed both LAT1 and ATB 0,+ . Moreover, we validated their targeting capabilities and elucidated the transport mechanism of LAT1 and ATB 0,+ -mediated endocytosis. The tumor inhibition rate of tyrosine-modified liposomes greatly increased from 39% to 87% compared with commercially available liposomes loaded CPT-11(Onivyde®). Overall, it showed a good application prospect for efficient tumor therapy and industrial production.
研究领域:
药学
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肿瘤学
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药物递送
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高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2020
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IF 4.845
Zhenjie Wang,Xinxin Lin,Dongxu Chi,Zhaochu Xu,Guimei Lin,Hongzhuo Liu,Jin Sun,Zhonggui He,Yongjun Wang
Along with the malignant proliferation of tumor requiring nutrients, the expression of L-type amino acid transporter 1(LAT1) and amino acid transporter B 0,+ (ATB 0,+ ) in cancer cells is up-regulated that can be used as new targets for active targeting of tumor. However, since normal cells also express amino acid transporters in small amounts, traditional ligand-exposure drug delivery systems are potentially toxic to the body. Therefore, we designed a smart-response drug delivery system that buries the tyrosine ligand in PEG hydration layer at normal tissues and exposes the ligand by cleaving the pH-sensitive bond of PEG at the tumor site. Irinotecan (CPT-11) is actively loaded into the inner aqueous phase of liposomes via a copper ion gradient mechanism which has high encapsulation efficiency and stable drug release profile. Smart-response liposomes showed the strongest cytotoxicity and the maximum cellular uptake in vitro , the largest amount of tumor site accumulation and the best antitumor effect in vivo , compared with non-targeted liposomes and non-sensitive liposomes. It is worth noting that smart-response liposomes not only achieved enhanced antitumor effect but also attenuated side effects compared to ligand-exposure liposomes. This provides a smart responsive drug delivery system for precise treatment and shows a good application prospect.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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高影响因子
ACS Applied Materials & Interfaces
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2020
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IF 8.758
Longfa Kou,Rui Sun,Xinyu Jiang,Xinlu Lin,Huirong Huang,Shihui Bao,Youting Zhang,Chao Li,Ruijie Chen,Qing Yao
Tumor cells usually display metabolic, genetic, and microenvironment-related alterations, which are beneficial to tumor proliferation, tumor development, and resistance occurrence. Many transporters and enzymes, including ATB0,+, xCT, and matrix metalloproteinases (MMPs), are involved in the altered cell metabolism and tumor microenvironment and often abnormally upregulated in malignant tumors. Meanwhile, these dysregulated transporters and enzymes provide targets not only for a pharmacological blockage to suppress tumor progress but also for tumor-specific delivery. Although transporters and MMPs have been widely reported for antitumor drug delivery, the feasibility of utilizing two strategies has never been elucidated yet. Herein, we developed an MMP2-activated and ATB0,+-targeted liposome with doxorubicin and sorafenib (DS@MA-LS) loaded for optimal tumor drug delivery for cancer therapy. DS@MA-LS was designed to prolong blood circulation and deshield the PEG shell from MMP2 cleavage to expose lysine and target overexpressed ATB0,+ for enhanced tumor distribution and cancer cellular uptake. Besides the anticancer effects of loaded drugs, the endocytosed liposomes could further increase ROS production and suppress the antioxidant system to amplify oxidative stress. As expected, DS@MA-LS displayed enhanced targeted drug delivery to tumor sites with the MMP2-controlled ligand exposure and ATB0,+-mediated uptake. More importantly, DS@MA-LS successfully inhibited the tumor growth and cancer cell proliferation both in vitro and in vivo by enhancing apoptosis and ferroptosis, which thanks to the increased ROS generation and impaired GSH synthesis synergistically amplified oxidative stress. Our results suggested that the tumor microenvironment-responsive, multistaged nanoplatform, DS@MA-LS, has excellent potential for optimal drug delivery and enhanced cancer treatment.
研究领域:
药学
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纳米技术
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癌症研究
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生物医学工程
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